BRIEF REPORT
Early histologic findings of pulmonary SARS-CoV-2 infection detected
in a surgical specimen
Angelina Pernazza1&Massimiliano Mancini2&Emma Rullo3&Massimiliano Bassi4&Tiziano De Giacomo4& Carlo Della Rocca1&Giulia d’Amati3
Received: 2 April 2020 / Revised: 11 April 2020 / Accepted: 26 April 2020
#Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract
Despite the current pandemic season, reports on pathologic features of coronavirus disease 19 (Covid-19) are exceedingly rare at the present time. Here we describe the pathologic features of early lung involvement by Covid-19 in a surgical sample resected for carcinoma from a patient who developed SARS-CoV-2 infection soon after surgery. The main histologic findings observed were pneumocyte damage, alveolar hemorrhages with clustering of macrophages, prominent and diffuse neutrophilic margin-ation within septal vessels, and interstitial inflammatory infiltrates, mainly represented by CD8+ T lymphocytes. These features are similar to those previously described in SARS-CoV-2 infection. Subtle histologic changes suggestive pulmonary involvement by Covid-19 may be accidentally encountered in routine pathology practice, especially when extensive sampling is performed for histology. These findings should be carefully interpreted in light of the clinical context of the patient and could prompt a pharyngeal swab PCR test to rule out the possibility of SARS-CoV-2 infection in asymptomatic patients.
Keywords SARS-CoV-2 . Covid-19 . Pathology . Lung histology
Introduction
Coronavirus disease 19 (Covid-19) is a global pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). According to the WHO Covid-19 situation report of March 29, Italy is the most affected European country, with 92.472 total cases and 10.023 deaths. The virus is transmitted mainly by inha-lation of respiratory droplets from both symptomatic and asymptomatic patients. Fever, fatigue, and dry cough are the most common symptoms at clinical presentation.
Approximately 13–20% of infected individuals develop severe respiratory symptoms with radiological findings of interstitial involvement, requiring assisted oxygena-tion [1–3]. A low number of routine autopsies is per-formed due to the high infectivity of the disease; ac-cordingly, there are only a few reports in medical liter-ature describing the histopathologic findings of SARS-CoV-2 infection [4, 5]. More in-depth investigations on-ly come from SARS-Coronavirus outbreaks in the past [6].
Here we describe the histologic features of early lung in-volvement by Covid-19 in a surgical sample resected for car-cinoma from a patient who later developed SARS-CoV-2 infection.
Case report
A 61-year-old male smoker was admitted to our hospital for surgical treatment of a lung adenocarcinoma, diag-nosed on biopsy. His clinical history was positive for a MALT lymphoma diagnosed 6 months before, with complete remission after therapy. According to pre-operatory imaging, obtained 3 weeks before surgery,
* Giulia d’Amati
giulia.damati@uniroma1.it
1 Department of Medico-Surgical Sciences and Biotechnologies, Polo
Pontino-Sapienza University, 04100 Latina, Italy
2
Division of Morphologic and Molecular S. Andrea Hospital, Sapienza, University of Rome, 00189 Rome, Italy
3
Department of Radiological, Oncological and Pathological Sciences, Sapienza, University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy
4 Department of General and Specialistic Surgery“P. Stefanini”,
Sapienza, University of Rome, 00161 Rome, Italy https://doi.org/10.1007/s00428-020-02829-1
the lesion was localized in the right inferior lobe, mea-sured 2 cm and showed a solid appearance. There were no ground glass opacities. At admission, the patient was in good general condition, afebrile. A thoracoscopic lo-bectomy with lymph node dissection (stations 2, 4, 7, 8, 9, and 10) was performed, without intraoperative com-plications. After surgery, the patient developed progres-sive lymphopenia (with values ranging between 920 and 340 lymphocytes/μL from the first to the fifth post-operative day) and, on the scheduled date for discharge, had an episode of fever (38 °C) in the absence of re-spiratory symptoms. Thus, his antibiotic therapy was changed, with no improvement. A pharyngeal swab PCR test was performed, which confirmed the suspicion of SARS-CoV-2 infection. The patient was immediately transferred to the isolation ward where he developed cough, dyspnea, fatigue, and high fever (38–39 °C). SpO2 was stable between 96 and 98%. Both white blood cells (2570/μL) and lymphocytes counts were low (280/μL). A chest CT scan showed post-resection changes and bilateral, peripheral, and ill-defined ground-glass opacities, mainly involving the lower lobe, consis-tent with Covid-19 pneumonia (Fig. 1a).
Since oxygen saturation had dropped to 35%, he re-ceived supplemental oxygen through a CPAP mask. On a second CT scan, performed 1 week later, the ground-glass opacities were enlarged, with areas of consolidation (Fig. 1b). He received a therapy based on antibiotics (meropenem and bactrim), antiviral drugs (acyclovir and darunavir), and on two recently approved experimental
drugs for SARS-CoV-2 infection: tocilizumab (commonly used for the therapy of rheumatoid arthritis) and chloro-quine hydrate (a common antimalarial drug), with an im-provement of his conditions and clinical remission in the following weeks.
Histologic examination of the formalin-fixed specimen confirmed the diagnosis of lung adenocarcinoma, with a pre-dominant acinar pattern. The lung parenchyma surrounding the neoplasia showed diffuse hemorrhages and clusters of al-veolar macrophages, with occasional multinucleated cells (Fig.2a). At higher magnification, there was evidence of both diffuse pneumocyte loss and reactive hyperplasia, with focal pneumocytes showing nuclear inclusions (Fig.3a, b). There were scanty fibrin depositions on the alveolar surfaces, in the absence of hyaline membranes (Fig. 2c). The interstitium showed edema and a mild inflammatory infiltrate, mainly composed of cytotoxic (CD8+) T lymphocytes (Fig. 3c–f). Interestingly, there were diffuse aspects of neutrophil margin-ation within small arterioles (Fig. 3d). Occasional fibrous plugs were also observed (Fig.3c). Interstitial changes were more marked in the subpleural area, where mild fibrous thick-ening of alveolar septa was also observed (Fig.2b).
Finally, areas of smoking-related interstitial fibrosis, con-sistent with the patient’s habits, were also present.
Discussion
In this report, we provide a detailed analysis of the early histologic changes of pulmonary SARS-CoV-2 infection.
Fig. 1 High-resolution CT scans performed one (a)and two (b) weeks after surgery, respectively show ground glass bilateral opacities, enlarging with
Fig. 2 a(× 20) Alveolar hemorrhages and clusters of macrophages with occasional giant cells (arrow).b(× 10) The alveolar septa show mild fibrous thickening limited to the subpleural area.c(× 10) Fibrin deposits admixed with red blood cells and inflammatory infiltrates (H&E)
Similar to the two previously published cases from China [5], the virus-related alterations were an incidental finding in a surgical sample sent to the Pathology Department for routine diagnostic work-up of lung cancer, before the on-set of clear clinical signs and symptoms of Covid-19. As early radiological changes have been demonstrated in the asymptomatic phase of infection [7], we emphasize the importance of recognizing early subtle histological chang-es in lung surgical specimens.
The main histologic findings herein described are pneumocyte damage, alveolar hemorrhage and clustering of macrophages, and interstitial inflammatory infiltrates, with prominent and diffuse neutrophilic margination within septal vessels. These features are similar to those described in SARS-CoV-2 infection and are consistent with the previously postulated mechanisms underlying pulmonary damage in SARS [8, 9]: the interaction between the virus and both pneumocytes and alveolar macrophages triggers a cascade of immunological events, with the production of cytokines and
Fig. 3 a(× 40) Pneumocyte desquamation (arrow) and reactive
hyper-plasia with focal nuclear inclusion (asterisk). Abundant hemosiderin pig-ment is present within alveolar macrophages. b(× 40) Diffuse pneumocyte loss (arrows) and alveolar septal thickening.c(× 40) Inflammatory infiltrates and fibrous plugs as those observed in organizing
pneumonia (arrow).d(× 40) Neutrophilic vascular margination and ede-ma of the alveolar wall.eDiffuse interstitial lymphocyte infiltrate and intra-alveolar macrophages (H&E).f(× 20) CD8 immunostaining shows a prevalence of cytotoxic T lymphocytes (immunoperoxidase stain)
chemokines and expression of adhesion molecules by pneumocytes. This in turn drives an inflammatory response with prominent macrophages, neutrophils, and T CD8+ lym-phocytes, which is responsible for the diffuse alveolar damage observed in the more severe and advanced stage of the disease. Indeed, diffuse alveolar damage (DAD) has been reported as a common autopsy finding in SARS-CoV [6,10–13]. A recent autopsy report highlights the finding of diffuse alveolar dam-age as the major lung feature also in severe SARS-CoV-2 infection [4]. However, the absence of DAD does not rule out the possibility of Covid-19 pneumonia, in the early stage of disease [12].
Interestingly, in our case, histologic findings were more marked and diffused in the subpleural region. This is consis-tent with the higher frequency of peripheral and subpleural involvement on high-resolution CT scan recently reported in a cohort of 81 patients with Covid-19 pneumonia [3].
Covid-19 has been shown to strike elderly patients with higher frequency and worse clinical outcome espe-cially in the presence of comorbidities (e.g., chronic obstructive pulmonary disease and malignancy) [14,
15]. A male predilection has also been recognized [14]. We speculate that the rapid disease evolution ob-served in our patient could be due to pre-existing lung alterations induced by smoking, although there are no evidences supporting a correlation between smoking and severity of the disease [16].
In conclusion, during the current pandemic season, subtle pulmonary histologic changes suggestive of SARS-CoV-2 in-fection may be accidentally encountered in routine pathology practice, especially if extensive sampling is performed for histology.
These findings should be carefully interpreted in light of the clinical context of the patient and could prompt a pharyn-geal swab PCR test to rule out the possibility of SARS-CoV-2 infection in asymptomatic patients.
Authors’contributions Pernazza Angelina contributed to the analysis of
the pathologic findings and to manuscript writing; Mancini Massimiliano contributed to the pathologic analysis and to manuscript writing; Rullo Emma contributed to the analysis of the pathologic findings and to man-uscript writing; Bassi Massimiliano collected and critically analyzed clin-ical data; De Giacomo Tiziano collected and critclin-ically analyzed clinclin-ical data; Della Rocca Carlo revised the work critically for important intellec-tual content; and d’Amati Giulia contributed to the analysis of the path-ologic findings and to manuscript writing.
Compliance with ethical standards
The study complies with ethical standards with both Institutions. The patient gave his informed consent.
Conflict of interest The authors declare that they have no conflict of
interest.
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